Pharmacology Consult: Updates on management of acute and recurrent pericarditis
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Key takeaways:
- Acute and recurrent pericarditis require medical management to improve morbidity and quality of life.
- Aspirin, NSAIDs and colchicine are the first-line therapies, while immunotherapies show promise as well.
Acute and recurrent pericarditis are the most common pericardial syndromes and represent an etiology of chest pain that is associated with substantial morbidity, decreased quality of life and, rarely, mortality.
There have been significant updates in the management of pericarditis in the past decade, including the publishing of the 2015 European Society of Cardiology guidelines for the diagnosis and management of pericardial diseases, landmark literature underscoring the importance of specific therapies, and the use of “immunotherapies” to treat pericarditis; including the use of the first FDA-approved drug to treat recurrent pericarditis in the U.S.
Given that there are advances in managing pericarditis, and there are currently no U.S. guidelines available, this article reviews the modern management of acute and recurrent pericarditis.
ASA/NSAIDs
Aspirin (acetylsalicylic acid [ASA]) or NSAIDs remain the foundation for management of acute and recurrent pericarditis. Although neither has ever been proved to ameliorate the disease process of pericarditis as monotherapy, the combination of ASA/NSAIDs with colchicine has been shown to reduce symptom duration and recurrence, and has been the standard of care that has been compared in landmark 21st century pericarditis trials. The 2015 ESC guidelines recommend concomitant use of high-dose ASA or NSAIDs with weight-based colchicine for both acute and recurrent pericarditis. Currently, no study has directly compared ASA or NSAIDs to another in terms of safety or efficacy. Given the paucity of comparative data, it is recommended to select an agent based on previous efficacy, tolerability and clinical considerations. Table 1 describes suggested dosing of ASA/NSAID used in landmark trials. Duration of initial therapy with ASA/NSAIDs may range from 2 to 4 weeks in uncomplicated, acute cases, and may extend to several months in recurrent cases, before tapering. Tapering should be based on symptom resolution and C-reactive protein normalization, usually over 3 to 4 weeks.
NSAIDs such as ketorolac tromethamine and naproxen may be suitable alternatives to those listed within Table 1 below, but data regarding these agents are limited to case reports and cohort studies. For example, ketorolac tromethamine is a parenteral NSAID that may be reasonable in patients who have been receiving oral ASA/NSAIDs in the hospital, but are not experiencing pain relief. Clinical considerations, especially concomitant disease states, should be evaluated for selection of initial therapy. Generally, patients with preexisting CV or renal disease should receive ASA preferentially, due to the increased risk for CV and cerebrovascular events as well as decreased renal function associated with NSAIDs. Another consideration is the known propensity for ASA/NSAID therapy to cause gastrointestinal ulceration. In all of the pericarditis landmark trials, investigators used pharmacotherapy for gastroprotection, specifically proton pump inhibitors. Omeprazole 20 mg per day or misoprostol 600 µg to 800 µg per day has been recommended to reduce the risk for developing gastrointestinal ulcers. Misoprostol should be used cautiously, as diarrhea associated with its use may mask the presence of colchicine toxicity, which also presents as diarrhea.
Colchicine
Colchicine’s anti-inflammatory mechanisms are facilitated by tubulin disruption, which hinders mitotic proliferation of inflammatory cells, as well as chemotaxis and phagocytosis. However, other mechanisms are becoming the focus of clinical and translational research. A relatively recent in vitro monocyte model has shown that colchicine can suppress the nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a complex that mediates inflammation involved in the release of cytokines, including interleukin (IL)-1-beta. Although the precise pathophysiologic mechanism by which pericarditis occurs is nebulous, recent immunohistochemical evidence has linked pericarditis to significant upregulation of the NLRP3 inflammasome in human pericardial tissue. Moreover, the mechanism by which colchicine suppresses the NLRP3 inflammasome is not fully understood. It is likely to be a source of innovation in pericarditis treatment in the near future.
Clinically, colchicine has been shown to be efficacious in reducing recurrence and symptom persistence at 72 hours when used with ASA or NSAIDs in multiple studies, resulting in its use as a first-line agent in both acute and recurrent pericarditis. The 2015 ESC guidelines recommend using 0.5 mg colchicine twice daily (reduced to once daily if weight 70 kg and/or if the patient experiences adverse effects) for 3 months in acute pericarditis, and for at least 6 months in recurrent. Recently, a 0.5 mg tablet formulation of colchicine was approved by the FDA in June, albeit not indicated for pericardial diseases. An oral liquid dosage form of colchicine was available in the U.S., but was discontinued by its manufacturer in January 2022.
Clinical considerations of note include colchicine’s dosage-form specific contraindications. Colchicine is a P-glycoprotein (P-gp) and CYP3A4 substrate. The oral tablet is contraindicated in patients with hepatic or renal impairment when used concomitantly with a P-gp inhibitor or a strong CYP3A4 inhibitor. (See Table 2 below) The oral capsule is contraindicated in patients with hepatic or renal impairment when used concomitantly with foods such as grapefruit juice or medications, which are dual inhibitors of P-gp and CYP3A4 (Table 2), and also in patients with coexisting hepatic and renal impairment.
It is important to note that colchicine is considered off-label for the management of pericarditis. Therefore, prescribing information for either dosage form does not define the level of hepatic or renal impairment that warrant contraindication in patients with pericarditis. For other indications of colchicine, a creatinine clearance of 50 mL to 80 mL per minute is defined as “mild” impairment, and might be used considered the cutoff in terms of contraindication. No specific criteria or scoring system for hepatic impairment is used, only being described on a spectrum from mild to severe, and no specific dosing adjustments are given. Such contraindications are important, as colchicine has a high propensity to interact with other medications and has a narrow therapeutic index that could result in significant adverse effects and life-threatening toxicity.
Glucocorticoids
The 2015 ESC guidelines recommend use of glucocorticoids in patients with contraindications to first-line therapies, as a second-line option in the case of intolerance to colchicine and/or ASA/NSAIDs, or an incomplete response to this first-line therapy in patients with recurrent pericarditis, all after infectious causes have been ruled out. Low-dose glucocorticoids (0.2-0.5 mg/kg/day prednisone equivalent) should be used, as evidence suggests that glucocorticoid use is an independent risk factor for recurrence, is associated with serious adverse effects, and that patients can become dependent on glucocorticoids, requiring monthslong tapers to lower the risk for recurrence.
Immunotherapies
Since 2011, clinicians have been challenged with the management of patients with recurrent pericarditis, who presented with significant disease burden of pericarditis. This includes patients with multiple recurrences of pericarditis, who are unable to be weaned off of glucocorticoids, and/or patients who are receiving ASA/NSAIDs, colchicine and glucocorticoids and are unresponsive to such therapies. Therefore, the immunotherapies, or drugs that alter the inflammatory cascade through various mechanisms, have been trialed “off-label” from their traditional indications in patients with recurrent pericarditis.
The 2015 ESC guidelines recommend use of immunotherapies only for corticosteroid-dependent patients with recurrence, or those that would require unacceptably high doses, but it is important to note that extensive clinical trials have been conducted using immunotherapies since 2015. Since then, such immunotherapies provide a compelling alternative to glucocorticoids in patients who are intolerant to or have failed first-line therapies.
Immunotherapies include IL-1 receptor antagonists, azathioprine and IV immunoglobulin (IVIG). Case reports/series and systematic reviews have described the benefit of using IVIG in recurrent pericarditis, including an association with decreasing the risk of pericarditis recurrence. Azathioprine has similar and weaker data with respect to effect on recurrence of pericarditis, as well as an association with being able to taper glucocorticoids in patients. Stronger and more recent evidence exists regarding the use of IL-1 receptor antagonists, such as anakinra (Kineret, Sobi) and rilonacept (Arcalyst, Kiniksa Pharmaceuticals).
Anakinra is antagonist of the IL-1 receptor. Downstream antagonism of IL-1 produces inhibition of inflammatory cytokines, such as IL-1-alpha, IL-1-beta, prostaglandins, IL-6 and CRP. Anakinra has been associated with significantly decreasing recurrence rates and flares in patients with recurrent pericarditis. Recently, the IL-1-alpha and IL-1-beta “trap” rilonacept was FDA-approved for the prevention and treatment of recurrent pericarditis in adolescent and adult patients. Rilonacept acts as a decoy receptor and “traps” circulating IL-1-alpha and IL-1-beta from propagating inflammation downstream. In the landmark study using rilonacept, patients receiving rilonacept had significantly lower recurrence rates and pain scores, and were able to be weaned off all other background pericarditis therapies (including NSAIDs, colchicine and glucocorticoids). In adults, rilonacept is first administered as a 320 mg subcutaneous (SQ) loading dose, then as a 160 mg SQ once-weekly maintenance dose. Children and adolescents aged 12 to 17 years are administered a 4.4 mg/kg (maximum of 320 mg) SQ loading dose, then a 2.2 mg/kg (maximum of 160 mg) SQ maintenance dose, once weekly. Adverse effects associated with IL-1 antagonists namely include injection site reactions, infections and, potentially, hyperlipidemia. Given the COVID-19 pandemic, clinicians should screen patients for appropriate and updated vaccinations before initiating IL-1 antagonists in patients with pericarditis. Since limited data are available regarding the risks of secondary transmission of infection by live vaccines in patients receiving IL-1 antagonists, it is recommended to avoid administration of live vaccines during treatment. Given the current body of evidence regarding IL-1 antagonists and the serious adverse effects associated with glucocorticoids, some experts recommend initiating IL-1 antagonists earlier in the management of recurrent pericarditis.
A treatment strategy
Colchicine and ASA/NSAIDs should be used first-line for the management of acute and recurrent pericarditis. ASA/NSAIDs should be tapered over 3 to 4 weeks when signs and symptoms of pericarditis are resolved and CRP has returned to normal. Colchicine should be used for 3 months in acute pericarditis and for 6 months in recurrent pericarditis. Use of glucocorticoids has fallen out of favor due to adverse effects and long duration of use, but should be used sparingly at low doses. Immunotherapies, specifically IL-1 antagonists, may be considered earlier in therapy, given their ability to effectively wean off glucocorticoids and other pericarditis therapies, and relatively lower amount and severity of adverse effects, compared with glucocorticoids.
References:
- Adler Y, et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv318.
- Arcalyst (rilonacept) [package insert]. Kiniksa Pharmaceuticals (UK), Ltd. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125249s049lbl.pdf. Updated March 2021. Accessed Aug. 9, 2023.
- Brucato A, et al. JAMA. 2016;doi:10.1001.jama.2016.15826.
- Chiabrando J, et al. J Am Coll Cardiol. 2020;doi:10.1016/j.jacc.2019.11.021.
- Colcrys (colchicine, USP) tablets. Package insert. Takeda Pharmaceuticals America Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf. Updated November 2012. Accessed Aug. 9, 2023.
- Imazio M, et al. Ann Intern Med. 2011;doi:10.7326/0003-4819-155-7-201110040-00359.
- Imazio M, et al. Arch Intern Med. 2005;doi:10.1001/archinte.165.17.1987.
- Imazio M, et al. Circulation. 2005;doi:10.1161/CIRCULATIONAHA.105.542738.
- Imazio M, et al. Circulation. 2008;doi:10.1161/CIRCULATIONAHA.107.761064.
- Imazio M, et al. Eur Heart J. 2021;doi:10.1093/eurheartj/ehab221.
- Imazio M, et al. Eur J Prev Cardiol. 2020;doi:10.1177/2047487319879534.
- Imazio M, et al. J Cardiovasc Med (Hagerstown). 2016;doi:10.2458/JCM.0000000000000260.
- Imazio M, et al. Lancet. 2014;doi:10.1016/s0140-6736(13)62709-9.
- Imazio M, et al. N Engl J Med. 2013;doi:10.1056.NEJMoa1208536.
- Klein AL, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2027892.
- Leung YY, et al. Semin Arthritis Rheum. 2015;doi:10.1016/j.semarthrit.2015.06.013.
- Mauro AG, et al. JACC Basic Transl Sci. 2021;doi:10.1016/j.jacbts.2020.11.016.
- Mitigare (colchicine) capsules. Package insert. Hikma Pharmaceuticals USA Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204820s000lbl.pdf. Updated September 2014. Accessed Aug. 9, 2023.
- Schwier NC, et al. Heart Lung. 2021;doi:10.1016/j.hrtlng.2021.06.009.
- Schwier NC, et al. Pharmacotherapy. 2021;doi:10.1002/phar.2640.
- Schwier NC, et al. J Pediatr Pharmacol Ther. 2022;doi:10.5863/1551-6776-27.7.595.
- U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Updated Aug. 24, 2022. Accessed Aug. 9, 2023.
- Vianello F, et al. Int J Cardiol. 2011;doi:10.1016/j.ijcard.2011.01.027.
- Wendelin G, et al. Pediatr Cardiol. 2008;doi:10.1007/s00246-007-9025-y.
For more information:
Trenton Flanagan, PharmD, is a PGY-1 Pharmacy Resident at Baylor University Medical Center.
Nicholas C. Schwier, PharmD, BCPS-AQ Cardiology, is assistant dean of experiential education and clinical associate professor in the Office of Experiential Education/Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, at SUNY Binghamton.
Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Healio | Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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